Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.
Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Lancet. 2019 Aug 24;394(10199):672-683. doi: 10.1016/S0140-6736(19)31791-X.
A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease.
The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985.
Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; p=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33-0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up-ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group.
Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs.
Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.
固定剂量联合治疗（复方药策略）已被提议用于降低心血管疾病的负担，特别是在低收入和中等收入国家（LMICs）。PolyIran 研究旨在评估包括阿司匹林、阿托伐他汀、氢氯噻嗪、依那普利或缬沙坦在内的四组分复方药在一级和二级预防心血管疾病方面的有效性和安全性。
PolyIran 研究是一项两组成、实用、聚类随机试验，嵌套在 Golestan 队列研究（GCS）中，该队列研究有 50045 名年龄在 40-75 岁的参与者，来自伊朗的戈勒斯坦省。通过将（村庄）聚类随机分配（1:1）至非药物预防干预措施的单一方案组（最小护理组）或与每日一次的复方药片一起（复方药组）。随机分配按三个区（Gonbad、Aq-Qala 和 Kalaleh）分层，以村庄为单位进行随机分配。我们使用了平衡随机分配算法，考虑了大小为 20 的块大小，并平衡了聚类大小或聚类大小的自然对数（取决于层内的偏度）。随机分配是在固定的时间点（2011 年 1 月 18 日）由英国伯明翰大学的统计学家完成的，与当地研究小组无关。非药物预防干预措施（包括关于健康生活方式的教育培训，例如低盐、低糖、低脂肪的健康饮食、运动、体重控制以及戒烟和禁鸦片）在第 3 个月和第 6 个月由 PolyIran 现场访问团队提供，然后每 6 个月提供一次。该研究使用了两种复方药片配方。参与者首先被开处方服用复方药一（氢氯噻嗪 12.5mg、阿司匹林 81mg、阿托伐他汀 20mg 和依那普利 5mg）。在随访期间出现咳嗽的参与者由经过培训的研究医生转换为复方药二，其中包含缬沙坦 40mg 代替依那普利 5mg。参与者随访 60 个月。主要心血管事件（包括因急性冠状动脉综合征住院、致命性心肌梗死、猝死、心力衰竭、冠状动脉血运重建术以及非致死性和致死性中风）的发生是由 GCS 随访团队进行中心评估的，该团队对分配情况进行了盲法评估。我们通过包括两组研究中符合资格标准的所有参与者进行了意向治疗分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01271985。
2011 年 2 月 22 日至 2013 年 4 月 15 日期间，我们共招募了 6838 名参与者进入研究-最小护理组 3417 名（116 个聚类），复方药组 3421 名（120 个聚类）。在复方药组的 3421 名参与者中，有 1761 名（51.5%）为女性，最小护理组的 3417 名参与者中有 1679 名（49.1%）为女性。服用复方药片的中位依从性为 80.5%（IQR 48.5-92.2）。在随访期间，最小护理组的 3417 名参与者中有 301 名（8.8%）发生了主要心血管事件，而复方药组的 3421 名参与者中有 202 名（5.9%）（校正后的危险比[HR]0.66，95%CI0.55-0.80）。我们没有发现存在（HR0.61，95%CI0.49-0.75）或不存在（0.80；0.51-1.12；p=0.19）先前存在的心血管疾病与主要心血管事件发生之间存在统计学显著交互作用。当限制在服用复方药且依从性高的参与者中时，与最小护理组相比，主要心血管事件的风险降低更大（校正后的 HR0.43，95%CI0.33-0.55）。两组研究中不良事件的发生频率相似。在 5 年的随访期间报告了 21 例颅内出血-10 例在复方药组，11 例在最小护理组。复方药组有 13 例经医生确诊的上消化道出血，最小护理组有 9 例。
复方药的使用在预防主要心血管事件方面是有效的。药物的依从性很高，不良事件的数量也很低。复方药策略可被视为控制心血管疾病的另一种有效手段，特别是在 LMICs。
德黑兰大学医学科学、Barakat 基金会和 Alborz Darou。
